PACAP-LOADED LIPOSOME DELIVERY ACROSS THE BBB: A LIGHT-SHEET MICROSCOPY STUDY

The blood-brain barrier (BBB) impermeability and selectivity prevent the transport of many therapeutic molecules into the brain, making ineffective their use for treatment of neurological diseases.1 Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuroprotective peptide proposed for treatment of central nervous system (CNS) diseases.2 However, its clinical use is limited by the efflux component of peptide transport system-6 (PTS-6), which reduces its brain uptake3, and also for its low stability in human plasma, rapid degradation and peripheral actions.4 Nanocarrier-mediated method is a non-invasive strategy to explore for brain drug delivery; among them, liposomes are attractive tools that can be easily modified to improve their delivery. 5 We developed liposomes loaded with PACAP and functionalized on the surface with gH625 peptide, a membrane-perturbing domain in glycoprotein H of Herpes simplex virus 1. gH625 can traverse the membrane bilayer and deliver several cargoes across cell membranes in vitro6 and crosses the BBB in vivo.7We evaluated the efficiency of gH625-liposomes to deliver PACAP to the brain in Swiss CD1 mice after intravenous administration using light sheet fluorescence microscopy. Our results show that gH625-liposomes ameliorate both PACAP reaching and crossing the BBB, increasing the number of neuronal cells labeled with PACAP. These data suggest that gH625-liposomes represent a promising strategy to deliver therapeutic agents to CNS for the treatment of neurological diseases but also to provide an effective imaging and/or diagnostic tool for the brain